Antengene Corporation, a leading innovative biopharmaceutical company, announced that the first patient has been dosed in a phase II trial (BUNCH) in China of ATG-008 (onatasertib), a second-generation mTORC1/2 inhibitor, for the treatment of advanced solid tumors harboring NFE2L2, STK11, RICTOR or other specific genetic alterations. The purpose of the single-arm, open-label trial is to evaluate the safety and efficacy of ATG-008 in patients with such advanced solid tumors that may be predictably sensitive to inhibition of mTORC1/2.
According to the latest report by the World Health Organization, there were an estimated 19.3 million newly diagnosed cancer cases and 10 million cancer-related mortalities in 2020 globally. Furthermore, the report also projected a 47% increase in cancer-related disease burden in the coming 20 years. China now ranks number one in both cancer incidence and mortality rates. This reminds us of the daunting challenges in cancer treatment and the ever more urgent need for effective novel anti-cancer therapies in China.
There is a close association between the mTOR signaling pathway and genetic mutations in NFE2L2, STK11 and RICTOR. ATG-008, a potent selective inhibitor of mTOR kinase that is currently under clinical development, may induce the cell death of multiple tumor types through the dual-inhibition of mTORC1 and mTORC2. Therefore, mTOR inhibitor ATG-008 has the potential to offer a new treatment option for patients with advanced solid tumors with such genetic alterations. Moreover, preclinical and clinical data also demonstrated the potent antitumor activity of ATG-008 in multiple tumor types.
Dr. Jay Mei, founder, chairman and CEO of Antengene, commented: “There are urgent needs for more effective treatment options for patients with various advanced solid tumors. We believe ATG-008 has strong potential to address a serious unmet medical need in a hard-to-treat group of cancers. This trial also marks an important step in the development of our innovative pipeline for the treatment of patients with solid tumors in China. We look forward to producing important clinical data to guide the further development and continue to demonstrate Antengene's leadership in drug development for mTORC1/2 inhibitors.”
Antengene has initiated several clinical trials in China and other Asia Pacific countries and regions with ATG-008 in the treatment of advanced hepatocellular carcinoma (HCC), advanced non-small-cell lung cancer (NSCLC) and in combination with an anti-PD-1 antibody in advanced solid tumors including hepatocellular carcinoma (HCC).
ATG-008 (onatasertib) is a second-generation mTORC1/2 inhibitor, for which development and commercialization rights in Asia Pacific were licensed from Celgene (now Bristol Myers Squibb). ATG-008 is currently being studied in multi-regional clinical trials for the treatment of advanced hepatocellular carcinoma (HCC), as well as non-small-cell lung cancer (NSCLC), advanced solid tumors harboring NFE2L2, STK11, RICTOR or other specific genetic alterations and other cancers as a single agent or in combination with an anti-PD-1 antibody
Antengene Corporation Limited announced the dosing of the first patient in China in a phase I/II trial (the HATCH trial) of eltanexor (ATG-016), a next-generation selective inhibitor of nuclear export (SINE) compound, for the treatment of intermediate and higher-risk myelodysplastic syndrome (MDS) according to the Revised International Prognostic Scoring System (IPSS-R) after failed treatment with hypomethylating agent (HMA) based therapies. This single-arm, open-label clinical trial is designed to evaluate the safety and efficacy of eltanexor monotherapy in the prespecified patients with MDS.
MDS is a malignancy originated in the bone marrow hemopoietic stem-cells of which the incidence increases significantly with age. The median overall survivals (OS) of patients with intermediate, high, and very high-risk MDS are 3, 1.6, and 0.8 years, respectively, and patients at these risk levels have a high probability of progressing to acute myeloid leukemia (AML). HMAs including azacytidine and decitabine are standard of care treatments for MDS. However, HMAs does not eradicate neoplastic clones and only generate response in around 50% of patients with MDS. Patients with MDS refractory to HMA-based therapies have a poor prognosis, limited options for follow-up treatment, and a median OS of only about four to six months.
Eltanexor is a next-generation SINE compound, and an antagonist of the nuclear export protein XPO1, of which expression correlates with a poor prognosis and resistance to chemotherapies. Eltanexor induces apoptosis in tumor cells by inhibiting XPO1 and has demonstrated favorable anticancer activity in xenograft models of hematological malignancies and solid tumors.
Data from a phase I/II clinical study of eltanexor in patients with higher-risk MDS refractory to HMAs, as presented at the 2019 American Society of Hematology (ASH) Annual Meeting, have demonstrated an objective response rate (ORR) of 35%, with bone marrow complete response (mCR) achieved by all of those patients assessed as ORR. Meanwhile, these clinical results of eltanexor also showed a favorable safety and tolerability profile. In addition to MDS, eltanexor is also being investigated for the treatment of advanced solid tumors in China.
“We are encouraged by the dosing of the first MDS patient in the HATCH trial, as it marks the beginning of the clinical development of our second SINE compound,” said Dr. Jay Mei, founder, chairman and CEO of Antengene. “Eltanexor was found to be safe and well tolerated in preclinical studies and showed potent anti-cancer activity in xenograft models, and demonstrated preliminary clinical efficacy and well tolerated safety profile in patients with high risk MDS. We are eager to explore the therapeutic potential of eltanexor and to continue working with regulators as we advance this clinical program with the goal of benefiting patients with intermediate and higher-risk MDS in China.”
Eltanexor is a next-generation selective inhibitor of nuclear export (SINE) compound. Compared to the first-generation SINE compound, eltanexor has lower blood-brain barrier penetration and broader therapeutic window which allows more frequent dosing and a longer period of exposure at higher levels with better tolerability. Therefore, eltanexor may be used to target a broader range of indications. Antengene is currently conducting clinical trials of eltanexor in patients with myelodysplastic syndrome (MDS) or advanced solid tumors in China